- Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter
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Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylaminebased analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.
- Neudorfer, Catharina,Seddik, Amir,Shanab, Karem,Jurik, Andreas,Rami-Mark, Christina,Holzer, Wolfgang,Ecker, Gerhard,Mitterhauser, Markus,Wadsak, Wolfgang,Spreitzer, Helmut
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Read Online
- Asymmetric hydrogenation of 3-chloro-1-phenylpropan-1-one catalyzed by ruthenium complexes
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Abstract A ruthenium complex modified with (1S,2S)-1,2-diphenyl-1,2-ethanediamine efficiently catalyzes asymmetric hydrogenation of 3-chloro-1-phenylpropan-1-one in the presence of potassium hydroxide solution in isopropyl alcohol, specific optical rotation of the synthesized products reaching -24.6°. Effects of the reaction time, hydrogen pressure, and the alkali concentration on the reaction course have been elucidated.
- Liu, Yanmei,Tai, Yulei,Guan, Ruqi,Chao, Guoku,Ye, Caiping,Li, Haihua,Li, Xiaoyan,Zhao, Yajuan
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Read Online
- Enantioselective reduction of prochiral ketones with NaBH 4/Me2SO4/(S)-Me-CBS
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The enantioselective reduction of prochiral ketones with NaBH 4/Me2SO4/(S)-Me-CBS is described. Borane is generated in situ via the reaction of NaBH4 with Me 2SO4 in tetrahydrofuran, which
- Zhou, Yuhan,Gao, Guchao,Song, Yuming,Qu, Jingping
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Read Online
- Preparation method of cefamoxetine hydrochloride
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The invention discloses a preparation method of tamoxidectin hydrochloride, belongs to the technical field of drug synthesis, and uses 3 - chlorine -1 - phenylpropanone as a raw material to undergo a reduction reaction. The synthesis route has the advantages of few reaction steps, mild reaction conditions,3 - simple 2 - operation, cheap -3 - and easily available raw materials, and low production cost 3 - and -1 - R-chloro - N - phenylpropanone is used as a raw material.
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Paragraph 0008; 0018; 0021; 0024; 0027
(2021/10/27)
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- Aza-Matteson Reactions via Controlled Mono-and Double-Methylene Insertions into Nitrogen-Boron Bonds
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Boron-homologation reactions represent an efficient and programmable approach to prepare alkylboronates, which are valuable and versatile synthetic intermediates. The typical boron-homologation reaction, also known as the Matteson reaction, involves formal carbenoid insertions into C-B bonds. Here we report the development of aza-Matteson reactions via carbenoid insertions into the N-B bonds of aminoboranes. By changing the leaving groups of the carbenoids and altering Lewis acid activators, selective mono- and double-methylene insertions can be realized to access various α- and β-boron-substituted tertiary amines, respectively, from common secondary amines. The derivatization of complex amine-containing bioactive molecules, diverse functionalization of the boronate products, and sequential insertions of different carbenoids have also been achieved.
- Xie, Qiqiang,Dong, Guangbin
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supporting information
p. 14422 - 14427
(2021/09/29)
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- Total Synthesis of Meayamycin B
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Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.
- Basu, Upamanyu,Bressin, Robert K.,Koide, Kazunori,Osman, Sami,Pohorilets, Ivanna
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supporting information
p. 4637 - 4647
(2020/05/01)
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- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
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Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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Page/Page column 37; 38
(2020/12/14)
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- Naphthyl-derived orthometalated RUII-NHC complexes: Effect of the NHC donors and/or substitution pattern on their synthesis and catalytic activity
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Naphthyl-derived orthometalated RuII-NHC complexes have been developed for catalytic applications considering the stereoelectronic profiles of the NHC ligands, which can be modified easily via alteration of the NHC donors (ImNHC/1,2,4tzNHC) as well as their substitution pattern at the naphthyl ring. The azolium salts [(2a?c)-H]Br, precursors for the NHC ligands, react with [Ru(p-cymene)Cl2]2 in the presence of a base to deliver the ortho-metalated RuII-NHC complexes 3a?c with the general formula [(NHC)Ru(p-cymene)Br]. Orthometalation in these complexes can be exploited for further functionalization of the NHC ligands. This is depicted by the generation of the diphenylethylene-inserted isolable intermediate complex 4, from the reaction of 3a with diphenylacetylene in a 1:1 ratio, which eventually provides an annulated salt 5a-Br via reductive elimination. Gratifyingly, this process can also be made catalytic, which directly provides several mono-/bis-annulated cationic N-heterocyclic compounds starting from the imidazolium salts [(2a,b)-H]Br using [Ru(p-cymene)Cl2]2 as a precatalyst. Furthermore, subtle variations in the electronic profiles of the complexes 3a?c in combination with steric alterations are observed to influence their activity in the transfer hydrogenation of acetophenone, a model for the hydride transfer process. Among all the complexes studied here, complex 3b with an ImNHC donor at the second position of the naphthyl ring was identified as a superior catalyst in comparison to 3a,c featuring either a different NHC donor or substitution pattern with a low loading of 0.1 mol%.
- Bauri, Somnath,Mallik, Anirban,Rit, Arnab
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p. 3362 - 3374
(2020/10/02)
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- Two enantiocomplementary ephedrine dehydrogenases from arthrobacter sp. TS-15 with broad substrate specificity
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The recently identified pseudoephedrine and ephedrine dehydrogenases (PseDH and EDH, respectively) from Arthrobacter sp. TS-15 are NADH-dependent members of the oxidoreductase superfamily of short-chain dehydrogenases/reductases (SDRs). They are specific for the enantioselective oxidation of (+)-(S) N-(pseudo)ephedrine and (-)-(R) N-(pseudo)ephedrine, respectively. Anti-Prelog stereospecific PseDH and Prelog-specific EDH catalyze the regio- A nd enantiospecific reduction of 1-phenyl-1,2-propanedione to (S)-phenylacetylcarbinol and (R)-phenylacetylcarbinol with full conversion and enantiomeric excess of >99%. Moreover, they perform the reduction of a wide range of aryl-aliphatic carbonyl compounds, including ketoamines, ketoesters, and haloketones, to the corresponding enantiopure alcohols. The highest stability of PseDH and EDH was determined to be at a pH range of 6.0-8.0 and 7.5-8.5, respectively. PseDH was more stable than EDH at 25 °C with half-lives of 279 and 38 h, respectively. However, EDH is more stable at 40 °C with a 2-fold greater half-life than at 25 °C. The crystal structure of the PseDH-NAD+ complex, refined to a resolution of 1.83 ?, revealed a tetrameric structure, which was confirmed by solution studies. A model of the active site in complex with NAD+ and 1-phenyl-1,2-propanedione suggested key roles for S143 and W152 in recognition of the substrate and positioning for the reduction reaction. The wide substrate spectrum of these dehydrogenases, combined with their regio- A nd enantioselectivity, suggests a high potential for the industrial production of valuable chiral compounds.
- Shanati, Tarek,Lockie, Cameron,Beloti, Lilian,Grogan, Gideon,Ansorge-Schumacher, Marion B.
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p. 6202 - 6211
(2019/08/15)
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- Synthesis of Benzylic Alcohols by C-H Oxidation
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Selective methylene C-H oxidation for the synthesis of alcohols with a broad scope and functional group tolerance is challenging due to the high proclivity for further oxidation of alcohols to ketones. Here, we report the selective synthesis of benzylic alcohols employing bis(methanesulfonyl) peroxide as an oxidant. We attempt to provide a rationale for the selectivity for monooxygenation, which is distinct from previous work; a proton-coupled electron transfer mechanism (PCET) may account for the difference in reactivity. We envision that our method will be useful for applications in the discovery of drugs and agrochemicals.
- Tanwar, Lalita,B?rgel, Jonas,Ritter, Tobias
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p. 17983 - 17988
(2019/11/14)
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- Heteroditopic Ru(II)-And Ir(III)-NHC Complexes with Pendant 1,2,3-Triazole/Triazolylidene Groups: Stereoelectronic Impact on Transfer Hydrogenation of Unsaturated Compounds
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Imidazol-2-ylidene (ImNHC) and 1,2,3-Traizol-5-ylidene (tzNHC) have been established as important classes of carbene ligands in homogeneous catalysis. To develop Ru(II)/Ir(III) complexes based on these ligand systems considering their electronic as well as steric profiles for hydride transfer reactions, we employed chelating ligands featuring combinations of ImNHC and triazole-N or mesoionic tzNHC donors bridged by a CH2 spacer with possible modifications at triazole backbone. In general, synthesized Ru(II) complexes were found to perform significantly better than analogous Ir(III) complexes in ketone and aldimine reduction. Among the Ru(II) complexes, electron-rich complexes 8/9 of the general formula [(p-cymene)(ImNHC-CH2-TzNHC)RuII(Cl)]BF4 with two different carbene donors (ImNHC and tzNHC) were found to perform appreciably better in ketone reduction than analogous complexes with a combination of ImNHC and triazole-N-donor ([(p-cymene)(ImNHC-CH2-Tz-N)RuII(Cl)]BF4; 4) explaining the electronic fine-Tuning of the catalytic systems. No appreciable variation in activity was observed between complexes 8 and 9 having almost similar electronic profiles. However, less bulky Ru(II) complex 9 with a triazole N-phenyl substituent is more suitable for aldimine reduction than is complex 8, having a triazole N-3,5-dimethylphenyl substituent that explains the steric influence in addition to electronic effect on the reduction process.
- Illam, Praseetha Mathoor,Donthireddy,Chakrabartty, Sayantan,Rit, Arnab
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supporting information
p. 2610 - 2623
(2019/07/31)
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- Iridium-Catalyzed Asymmetric Hydrogenation of Halogenated Ketones for the Efficient Construction of Chiral Halohydrins
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Iridium-catalyzed asymmetric hydrogenation of prochiral halogenated ketones was successfully developed to prepare various chiral halohydrins with high reactivities and excellent enantioselectivities under basic reaction condition (up to >99% conversion, 99% yield, >99% ee). Moreover, gram-scale experiment was performed well in the presence of just 0.005 mol% (S/C=20 000) Ir/f-amphox catalyst with 99% yield and >99% ee. (Figure presented.).
- Yin, Congcong,Wu, Weilong,Hu, Yang,Tan, Xuefeng,You, Cai,Liu, Yuanhua,Chen, Ziyi,Dong, Xiu-Qin,Zhang, Xumu
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supporting information
p. 2119 - 2124
(2018/04/30)
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- Ultrafast Iron-Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines, Oxaheterocycles, and Aminoalcohols
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A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h?1 at ?30 °C highlight the activity of this earth-abundant metal catalyst which tolerates a large number of functional groups.
- Blasius, Clemens K.,Vasilenko, Vladislav,Gade, Lutz H.
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p. 10231 - 10235
(2018/07/31)
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- 3'-chlorobenzene propanol synthesis process
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The invention relates to a 3'-chlorobenzene propanol synthesis process, which comprises the following concrete steps that 3'-chloropropiophenone and levo prolinol are sequentially added into 95-percent ethanol; after reaction liquid is completely dissolved, cooling is performed; potassium borohydride is added into reaction liquid in batches; heat insulation is performed after the addition is completed; after reaction liquid is subjected to heating and backflow reaction, the reaction liquid is subjected to pressure reduction concentration; n-hexane is added into the reaction liquid; heating isperformed; then, active carbon is added for heat insulation decoloration; reaction liquid is filtered; filter cake is eluted by the n-hexane; filter liquid is collected; the filter liquid is subjectedto crystallization and filtering; the filter cake is eluted by the n-hexane once; vacuum drying is performed to obtain the 3'-chlorobenzene. The final product of dextro 3'-chlorobenzene propanol is synthesized by using 3'-chloropropiophenone as a major raw material, using potassium borohydride as a reduction agent and using the levo prolinol as a catalyst. The produced 3'-chlorbenzene propanol isa dextro product; the crystallization temperature is higher than that of a mixed spinning product; the synthesis can be realized without needing a specific temperature reduction device; the energy consumption is reduced; the cost is reduced.
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Paragraph 0019; 0020; 0021
(2018/09/11)
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- Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization
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The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.
- Andresini, Michael,De Angelis, Sonia,Uricchio, Antonella,Visaggio, Angelica,Romanazzi, Giuseppe,Ciriaco, Fulvio,Corriero, Nicola,Degennaro, Leonardo,Luisi, Renzo
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p. 10221 - 10230
(2018/08/01)
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- Stereoselectivity arone derivatives of hydrogenation method
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The invention discloses a highly stereoscopic selective hydrogenation method for aromatic ketone derivatives. The method comprises the following steps: (1) placing a metal precursor [RhCl2Cp*]2 and a ligand shown in the formula (XIV) into a reaction vesse
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Paragraph 0095; 0096; 0097; 0098; 0099
(2017/10/20)
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- Efficient Synthesis of (R)-2-Chloro-1-(2,4-dichlorophenyl)ethanol with a Ketoreductase from Scheffersomyces stipitis CBS 6045
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By enzyme screening, a ketoreductase cloned from Scheffersomyces stipitis CBS 6045 and named SsCR was identified that could catalyze the asymmetric hydrogenation of a variety of aromatic ketones. SsCR exhibited a specific activity of 65 U mg?1p
- Shang, Yue-Peng,Chen, Qi,Kong, Xu-Dong,Zhang, Yu-Jun,Xu, Jian-He,Yu, Hui-Lei
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supporting information
p. 426 - 431
(2017/02/10)
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- A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK
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Purpose: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. Methods: All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. Results: The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. Conclusions: We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.
- Rozentul, Naomi,Avrahami, Yosef,Shubely, Moran,Levy, Laura,Munder, Anna,Cohen, Guy,Cerasi, Erol,Sasson, Shlomo,Gruzman, Arie
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p. 2873 - 2890
(2017/10/13)
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- Effect of functional groups in organic chlorides on radical reduction with hydrostannane under microwave irradiation
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The effect of functional groups on the activation of molecules by microwave irradiation in the reduction of organic chlorides by Bu3SnH was investigated. The reactivity of a substrate with a hydroxy group increased under microwave heating conditions in comparison with conventional heating.
- Nishimoto, Yoshihiro,Yazawa, Satoshi,Kiyokawa, Kensuke,Kajiki, Takahito,Tsukahara, Yasunori,Yamauchi, Tomohisa,Wada, Yuji,Baba, Akio,Yasuda, Makoto
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supporting information
p. 1116 - 1118
(2017/08/07)
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- A hydrochloric acid west reaches anchors the sandbank preparation method (by machine translation)
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The invention discloses a method for preparing west reaches anchors the sandbank hydrochloride, including 3 - chlorobenzene propanol, 1 - phenyl - 3 - (1 - naphthoxy) - 1 - propanol, preparation of pure west reaches anchors the sandbank, west reaches anchors the sandbank DTTA salt preparation, preparation of west reaches anchors the sandbank, hydrochloric acid west reaches anchors the sandbank crude preparation and hydrochloric acid west reaches anchors the sandbank preparation of the finished product, the invention, accelerate the speed of production, the saving in material. (by machine translation)
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Paragraph 0041; 0042; 0043
(2017/08/29)
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- Nearly aqueous-like activity of lipoprotein lipase treated with glucose-headed surfactant in organic solvent
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In this work, we explored the activation of a lipoprotein lipase from Burkholderia species by glucose-headed surfactants (GHSs) for enhancing its catalytic activity in organic solvent. Three GHSs were prepared and then tested as the additives for inducing the activation of lipoprotein lipase. The kinetic parameters of GHS-treated lipoprotein lipase were determined for the hydrolysis or alcoholysis of p-nitrophenyl acetate. It was found that GHS-treated lipoprotein lipase was 4 to 5 orders of magnitude more active than its native counterpart in organic solvent. Such a dramatic activity enhancement was largely the result of a huge increase in the turnover frequency kcat. Surprisingly, the kcat values in organic solvent were one order of magnitude greater than their aqueous counterparts. As a result, the kcat/Km of GHS-treated lipoprotein lipase in organic solvent became comparable to the aqueous level within one order of magnitude. We thus have demonstrated for the first time that a lipase can display nearly aqueous-like activity in organic solvent. As an illustrative application of GHS-treated lipoprotein lipase, we performed the dynamic kinetic resolution of two secondary alcohols, which provided the products of high enantiopurity (98–99%ee) with high yields (90–91%).
- Oh, Yeonock,Choi, Yoon Kyung,Yun, Inyeol,Lee, Eungyeong,Kim, Kyungwoo,Kim, Mahn-Joo
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p. 148 - 153
(2016/11/04)
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- Design, synthesis, and biological evaluation of novel thiazolidinediones as PPAR3/FFAR1 dual agonists
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Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPAR3 is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPAR3 and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.
- Darwish, Khaled M.,Salama, Ismail,Mostafa, Samia,Gomaa, Mohamed S.,Helal, Mohamed A.
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p. 157 - 172
(2016/01/16)
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- Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
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The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.(AA) Tomoxetine(BB) Fluoxetine(CC) 3-amino-1-propanol(DD) Nisoxetine(EE) DuloxetineCOPYRIGHT KIPO 2016
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Paragraph 0069-0072
(2016/12/01)
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- Chiral preparation method of dapoxetine hydrochloride key intermediate
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The invention discloses a chiral preparation method of a dapoxetine hydrochloride key intermediate.According to the preparation method, with 3-chloropropiophenone as a raw material and (+)2-ethylmorphine-B-chlorodiisopinocampherylborane Eap2BCl as a reduc
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Paragraph 0037; 0049; 0050
(2017/02/09)
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- Iminophenyl Oxazolinylphenylamine for Enantioselective Cobalt-Catalyzed Hydrosilylation of Aryl Ketones
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A new family of chiral iminophenyl oxazolinylphenylamines (IPOPA) was designed and synthesized through three steps from commercially available starting materials. An efficient cobalt-catalyzed asymmetric hydrosilylation of simple ketones with a low catalyst loading of CoCl2 and IPOPA was developed to afford chiral alcohols in good yields with high enantioselectivities.
- Chen, Xu,Lu, Zhan
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supporting information
p. 4658 - 4661
(2016/09/28)
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- A convenient enantioselective CBS-reduction of arylketones in flow-microreactor systems
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A convenient, versatile, and green CBS-asymmetric reduction of aryl and heteroaryl ketones has been developed by using the microreactor technology. The study demonstrates that it is possible to handle borane solution safely within microreactors and that the reaction performs well using 2-MeTHF as a greener solvent.
- De Angelis, Sonia,De Renzo, Maddalena,Carlucci, Claudia,Degennaro, Leonardo,Luisi, Renzo
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supporting information
p. 4304 - 4311
(2016/05/24)
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- Chiral N-heterocyclic carbene iridium catalyst for the enantioselective hydrosilane reduction of ketones
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Enantioselective reduction of ketones with (EtO)2MeSiH catalyzed by an in-situ generated N-heterocyclic carbene (NHC) Ir complex at room temperature has been developed. A series of benzimidazolium salts were synthesized and screened in the asymmetric hydrosilylation reaction. As a result, propiophenone was efficiently reduced by the combined catalytic system of [IrCl(cod)]2 and NHC-Ag complex derived from N-(1-naphthalenylmethyl)-substituted benzimidazolium salt L12, affording the corresponding alcohol in 92% yield and with 92% ee. Moreover, the evaluation of an Ir catalyst precursor showed that cationic [Ir(cod)2]BF4 complex could be used. Furthermore, the introduction of a chiral hydroxyamide side arm into the benzimidazolium salt was critical for the successful design of the NHC ligand.
- Manabe, Yoshiki,Shinohara, Kanako,Nakamura, Hanako,Teramoto, Hiro,Sakaguchi, Satoshi
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p. 138 - 145
(2016/06/15)
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- Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation-Borylation-Ring-Opening of Azetidinium Ions
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In situ generated 2-phenyl-azetidinium ylides react with boronic esters to form acyclic γ-dimethylamino tertiary boronic esters. The transformation is believed to involve the formation of a zwitterionic boronate, which subsequently undergoes ring-opening 1,2-migration, which is promoted by the relief of ring strain. Owing to the configurational instability of the initially formed ylides, which appear to be in equilibrium with the open-chain carbene form, the reaction is not stereospecific. The C-B bond of the γ-dimethylamino tertiary boronic esters can be transformed into a variety of functional groups (C-OH, C-vinyl, C-H, C-BF3), thus giving a diverse selection of 3-aryl-1-aminopropanes, which represent a privileged motif among drug molecules.
- Casoni, Giorgia,Myers, Eddie L.,Aggarwal, Varinder K.
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p. 3241 - 3253
(2016/09/12)
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- DOPAMINE D3 RECEPTOR ANTAGONISTS COMPOUNDS
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The disclosure is directed to novel dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, including treating drug dependency and psychosis.
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Page/Page column 325
(2016/05/19)
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- Sodium Bromide-Catalyzed Oxidation of Secondary Benzylic Alcohols Using Aqueous Hydrogen Peroxide as Terminal Oxidant
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A halide salt, hydroperoxide and AcOH catalyst system was applied to the oxidation of secondary benzylic alcohols. This simple system can be applied to a variety of secondary benzylic alcohols and scaled up for gram-scale preparation. High secondary benzylic alcohol selectivity of the present method is demonstrated in hydroxyketone synthesis. Based on several experimental results, a catalytic cycle for our oxidation is proposed.
- Komagawa, Hiromi,Maejima, Yukako,Nagano, Takashi
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supporting information
p. 789 - 793
(2016/03/09)
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- A combined computational and experimental investigation of the oxidative ring-opening of cyclic ethers by oxoammonium cations
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The propensity of oxoammonium cations to facilitate the oxidative ring-opening of cyclic ethers to their corresponding distal hydroxy ketones is investigated. The reaction has been evaluated using experimental and computational methods to gain deeper insight into trends in reactivity.
- Loman, Jacob. J.,Carnaghan, Emma R.,Hamlin, Trevor A.,Ovian, John M.,Kelly, Christopher B.,Mercadante, Michael A.,Leadbeater, Nicholas E.
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p. 3883 - 3888
(2016/05/24)
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- Cobalt-catalyzed asymmetric hydroboration of aryl ketones with pinacolborane
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The highly enantioselective cobalt-catalyzed hydroboration reaction of aryl ketones with HBpin was developed using iminopyridine oxazoline ligands. Halides, amines, ethers, sulfides, esters and amides are well tolerated under the mild reaction conditions, demonstrating its synthetic advantage. Substituted diaryl ketones could also be hydroborated with high enantioselectivity.
- Guo, Jun,Chen, Jianhui,Lu, Zhan
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supporting information
p. 5725 - 5727
(2015/03/30)
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- A method for preparing optically active 3-amino-1-phenylpropanol derivatives as an intermediate and a method for preparing optically active pharmaceutical products using the same
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The present invention relates to a method for preparing a 3-amino-1-phenylpropanol derivative having (R) or (S) optical activity with 80% or more of an enantiomeric excess (ee), which includes a step of performing an asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. The invention also relates to a method for preparing an optically active pharmaceutical product, which includes a step of preparing a (R)- or (S)-3-amino-1-phenylpropanol derivative, that is an intermediate, by using the catalyst.(AA) 3-amino-1-phenylpropanol(BB) Tomoxetine(CC) Nisoxetine(DD) FluoxetineCOPYRIGHT KIPO 2016
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Paragraph 0143; 0156-0158
(2016/11/09)
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- Identification of an ε-keto ester reductase for the efficient synthesis of an (R)-α-lipoic acid precursor
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Abstract A novel reductase (CpAR2) with unusually high activity toward an ε-keto ester, ethyl 8-chloro-6-oxooctanoate, was isolated from Candida parapsilosis. The asymmetric reduction of ethyl 8-chloro-6-oxooctanoate using Escherichia coli cells coexpressing CpAR2 and glucose dehydrogenase genes gave ethyl (R)-8-chloro-6-hydroxyoctanoate, a key precursor for the synthesis of (R)-α-lipoic acid, in high space-time yield (530 gL-1d-1) and with excellent enantiomeric excess (>99%). This bioprocess was shown to be viable on a 10-L scale. This method provides a greener and more cost-effective method for the industrial production of (R)-α-lipoic acid.
- Zhang, Yu-Jun,Zhang, Wen-Xia,Zheng, Gao-Wei,Xu, Jian-He
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supporting information
p. 1697 - 1702
(2015/06/02)
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- Identification of key residues in Debaryomyces hansenii carbonyl reductase for highly productive preparation of (S)-aryl halohydrins
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Key residues of Debaryomyces hansenii carbonyl reductase in the determination of the reducing activity towards aryl haloketones were identified through combinatorial mutation of conserved residues. This study provides a green and efficient biocatalyst for the synthesis of (S)-aryl halohydrins.
- Xu, Guo-Chao,Shang, Yue-Peng,Yu, Hui-Lei,Xu, Jian-He
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supporting information
p. 15728 - 15731
(2015/11/02)
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- Chiral terpene auxiliaries III: Spiroborate esters from (1R,2S,3R,5R)-3-amino-apopinan-2-ol as highly effective catalysts for asymmetric reduction of ketones with borane
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New spiroborate esters, derived from terpene amino alcohols, (S)-prolinol, and 2-aminoethanol, were employed as catalysts in the borane reduction of acetophenone and other aryl alkyl and halogenated ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to 98% ee. The influence of the amino alcohol and the diol moieties of spiroborate on the reaction selectivity was examined. The catalyst load, the nature of the solvent, the borane source, and the reaction conditions were also investigated.
- ?wiklińska, Marta,Krzemiński, Marek P.,Tafelska-Kaczmarek, Agnieszka
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p. 1453 - 1458
(2015/12/09)
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- Facile Protocol for Catalytic Frustrated Lewis Pair Hydrogenation and Reductive Deoxygenation of Ketones and Aldehydes
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A series of ketones and aldehydes are reduced in toluene under H2 in the presence of 5 mol % B(C6F5)3 and either cyclodextrin or molecular sieves affording a facile metal-free protocol for reduction to alcohols. Similar treatment of aryl ketones resulted in metal-free deoxygenation yielding aromatic hydrocarbons.
- Mahdi, Tayseer,Stephan, Douglas W.
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supporting information
p. 8511 - 8514
(2015/11/27)
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- PEG600-carboxylates as efficient reusable reaction media and acylating agents for the resolution of sec-alcohols
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Herein is presented a simple, attractive, and reusable methodology for one-pot resolution/separation of free sec-alcohols with enantiomeric excess (ee) values over 90% by the combination of sustainable acylating agents/solvents (polyethylene glycol derivatives) and an easily available and common biocatalyst (Candida antarctica lipase B, or CAL B) under irreversible conditions, along with a separation process by extraction or distillation. A scale-up reaction was carried out with the Fluoxetine precursor with ee values close to 90% for the R enantiomer.
- Monteiro, Carlos M.,Lourenco, Nuno M. T.,Ferreira, Frederico C.,Afonso, Carlos A. M.
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- Chemoenzymatic synthesis of fluoxetine precursors. Reduction of β-substituted propiophenones
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Five endophytic yeast strains isolated from edible plants were tested in the reduction β-chloro- and β-azidopropiophenone for the preparation of optically active fluoxetine precursors. The biotransformation rendered not only the corresponding chiral γ-substituted alcohols, but also unsubstituted alcohols and ketones. The product profile was studied and a plausible mechanism for the reductive elimination of the β-functional group is proposed.
- Coronel, Camila,Arce, Gabriel,Iglesias, Cesar,Noguera, Cynthia Magallanes,Bonnecarrere, Paula Rodriguez,Giordano, Sonia Rodriguez,Gonzalez, David
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- Enantioselective reduction of propiophenone formed from 3-chloropropiophenone and stereoinversion of the resulting alcohols in selected yeast cultures
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Biotransformation of 3-chloro-1-phenylpropan-1-one 1 in sixteen selected cultures of yeast strains has been carried out. For most of the biocatalysts studied the substrate was fully consumed after 1-9 h of transformation, with the exception of the culture of Saccharomyces brasiliensis KCh 905, in which after 24 h trace amounts of the substrate were still visible (2%). However, apart from the expected enantiospecific reduction of the substrate to 3-chloro-1-phenylpropan-1-ol 3, the main biotransformation products comprised of a dehalogenation product - propiophenone 2 and the product of its reduction - 1-phenylpropan-1-ol 4. It was only in the cultures of five strains: Saccharomyces brasiliensis KCh 905, Rhodotorula marina KCh 77, Candida parapsilosis KCh 909, Candida viswanathii KCh 120, and Saccharomyces cerevisiae KCh 464 that 3-chloro-1-phenylpropan-1-ol 3 was observed in amounts of more than 10% of the product mixture. (S)-3-Chloro-1-phenylpropan-1-ol with ee = 91% was identified after 9 h of biotransformation in the culture of Candida viswanathii KCh 120, whereas (R)-3-chloro-1-phenylpropan-1-ol with ee = 28% was found in the culture of Aphanocladium album KCh 417. 1-Day biotransformation of propiophenone 2 in the cultures of Rhodotorula strains gave (S)-1-phenylpropan-1-ol 4 with a very high ee (95-99%) and 85-99% of substrate conversion, whereas transformation of this substrate in the cultures of Candida viswanathii KCh 120 and Candida parapsilosis KCh 909 led to (R)-1-phenylpropan-1-ol with ee = 98% and 97%, respectively. During biotransformation of propiophenone the percent composition of the reaction mixtures changed with time. Employment of the racemic mixture of 1-phenylpropan-1-ol 4 as a substrate for biotransformations allowed us to observe that the biocatalysts tested were capable of enantioselective oxidation of (S)-1-phenylpropan-1-ol. An exception was the culture of Rhodotorula glutinis KCh 242, in which after one day of biotransformation (S)-1-phenylpropan-1-ol was obtained with ee = 96%.
- Janeczko, Tomasz,Kostrzewa-Suslow, Edyta
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p. 1264 - 1269
(2015/01/16)
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- Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine
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A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.
- Zhou, Ji-Ning,Fang, Qiang,Hu, Yi-Hu,Yang, Li-Yao,Wu, Fei-Fei,Xie, Lin-Jie,Wu, Jing,Li, Shijun
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p. 1009 - 1017
(2014/02/14)
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- Mesoporous silica KIT-6 supported superparamagnetic CuFe2O 4 nanoparticles for catalytic asymmetric hydrosilylation of ketones in air
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A diverse range of prochiral ketones were reduced in air with high yields and good-to-excellent enantioselectivities (up to 97% ee) in the presence of a heterogeneous catalyst system, which was in situ formed from catalytic amounts of superparamagnetic CuFe2O4 nanoparticles supported on mesoporous silica KIT-6 and non-racemic dipyridylphosphine ligand, the stoichiometric hydride donor polymethylhydrosiloxane (PMHS) as well as certain amounts of additives. The magnetically separable catalysts could be efficiently reused 4 times without apparent loss of both the activity and enantioselectivity. the Partner Organisations 2014.
- Li, Min,Li, Bin,Xia, Hong-Feng,Ye, Danru,Wu, Jing,Shi, Yifeng
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p. 2680 - 2688
(2014/05/06)
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- Asymmetric transfer hydrogenation of aromatic ketones catalyzed by new chiral C2-symmetric bis(sulfonyl) tetraaza ligands complexed with [Ru(η6-p-cymene)Cl2]2 in water
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In this report, a new series of C2-symmetric bis(sulfonyl) tetraaza ligands were synthesized from (1S,2S)-1,2-diarylethylenediamine analogues and tested in the asymmetric transfer hydrogenation (ATH) of aromatic ketones by complexing with [Ru(η6-p-cymene)Cl2]2 employing sodium formate as hydrogen source in neat water. A moderate to excellent conversion (~99.8 %) and overall satisfying enantioselectivity (~92.8 %) were obtained with varied electronic and steric effects of the substituents on ligands and substrates.
- Liu, Xungao,Zhang, Tian,Hu, Yingying,Shen, Liang
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p. 1289 - 1295
(2014/07/21)
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- Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes
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This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.
- Zenzola, Marina,Degennaro, Leonardo,Trinchera, Piera,Carroccia, Laura,Giovine, Arianna,Romanazzi, Giuseppe,Mastrorilli, Piero,Rizzi, Rosanna,Pisano, Luisa,Luisi, Renzo
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p. 12190 - 12200
(2015/03/31)
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- Facile access to chiral alcohols with pharmaceutical relevance using a ketoreductase newly mined from Pichia guilliermondii
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Chiral secondary alcohols with additional functional groups are frequently required as important and valuable synthons for pharmaceuticals, agricultural and other fine chemicals. With the advantages of environmentally benign reaction conditions, broad reaction scope, and high stereoselectivity, biocatalytic reduction of prochiral ketones offers significant potential in the synthesis of optically active alcohols. A CmCR homologous carbonyl reductase from Pichia guilliermondii NRRL Y-324 was successfully overexpressed. Substrate profile characterization revealed its broad substrate specificity, covering aryl ketones, aliphatic ketones and ketoesters. Furthermore, a variety of ketone substrates were asymmetrically reduced by the purified enzyme with an additionally NADPH regeneration system. The reduction system exhibited excellent enantioselectivity (>99% ee) in the reduction of all the aromatic ketones and ketoesters, except for 2-bromoacetophenone (93.5% ee). Semi-preparative reduction of six ketones was achieved with high enantioselectivity (>99% ee) and isolation yields (>80%) within 12 h. This study provides a useful guidance for further application of this enzyme in the asymmetric synthesis of chiral alcohol enantiomers. Copyright
- Xu, Guochao,Yu, Huilei,Xu, Jianhe
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p. 349 - 354
(2013/08/22)
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- Bronsted acid catalyzed asymmetric SN2-Type O-alkylations
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Bridging the gap: Bronsted acids catalyze an intramolecular S N2-type alkylation of alcohols with ethers by bridging a pentacoordinate transition state, thus simultaneously activating both the leaving group and nucleophile (see scheme). Density functional calculations provide detailed insight into the course of the reaction and the transition-state structure.
- Coric, Ilija,Kim, Ji Hye,Vlaar, Tjostil,Patil, Mahendra,Thiel, Walter,List, Benjamin
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supporting information
p. 3490 - 3493
(2013/05/09)
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- Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: Applications in the synthesis of reboxetine
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A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O- cyclohexylidene-d-glyceraldehyde in ~43% overall yields. The Royal Society of Chemistry.
- Dar, Abdul Rouf,Aga, Mushtaq A.,Kumar, Brijesh,Yousuf, Syed Khalid,Taneja, Subhash Chandra
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p. 6195 - 6207
(2013/09/12)
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- Corey-itsuno reduction of ketones: A development of safe and inexpensive process for synthesis of some API intermediates
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A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N,N-diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N,N-diethylaniline hydrochloride and (S)-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture enantiopure dapoxetine at the plant scale.
- Mahale, Rajendra D.,Chaskar, Sudhir P.,Patil, Kiran E.,Maikap, Golak C.,Gurjar, Mukund K.
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experimental part
p. 710 - 713
(2012/07/27)
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- Candida tenuis xylose reductase catalyzed reduction of aryl ketones for enantioselective synthesis of active oxetine derivatives
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Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1-phenyl-1-propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two-phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)-Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo-like kinase 1 inhibitor are discussed. Copyright
- Vogl, Michael,Brecker, Lothar,Kratzer, Regina,Nidetzky, Bernd
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p. 847 - 853,7
(2020/07/31)
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- Asymmetric total synthesis of (S)-dapoxetine
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A concise asymmetric total synthesis of (S)-dapoxetine from commercially available 3-chloropropiophenone is described. The key step includes a highly stereoselective amination of chiral benzylic ether, with the retention of stereochemistry, using chlorosu
- Kim, Sun Joo,Jeon, Tae Hong,Min, Im Sook,Kim, In Su,Jung, Young Hoon
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supporting information; experimental part
p. 3680 - 3682
(2012/09/25)
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